BACKGROUND OF THE INVENTION The present invention relates to compositions and methods useful for treating diarrhea, especially travelers' diarrhea.

Diarrhea is a major health problem, especially in and when traveling to developing countries. Treatment of diarrhea, especially travelers' diarrhea, typically include fluid replace- ment, symptomatic relief with absorbants and antimotility agents, and antimicrobial agents used for 3 to 5 days.

The article "Travelers' Diarrhea - Consensus Conference" (JAMA. May 10, 1985, 235(18), pages 2700-4) does not recommend antimicrobial agents for prevention of travelers' diarrhea in view of the potential for many .side effects from such widespread usage. The recommendation is rapid institution of effective treatment that can shorten the disease to 30 hours or less. For mild diarrhea, this publication recommends loperamide or diphenoxylate, and, alternatively, bismuth subsalicylate. Use of antimicrobial drugs, such as trimethoprim-sulfamethoxazole, trimethoprim alone, and doxycycline, are recommended for the more severe diarrhea cases. Oral rehydration is recommended when necessary.

In R. Longe, "Antidiarrheal and Other Gastrointestinal

Products" (Handbook of Nonprescription Drugs. Eiohth Edition. Chapter 5, pages 59-74, 1986; incorporated by reference herein in its entirety), types of diarrhea as well as various treatment methods are discussed. Pharmacologic agents described therein for use against diarrhea include opiates, polycarbophil, adsorbents, and anticholinergics. Combinations of agents, including bismuth- containing agents, are known and are described therein (at pages

73-74), and include: paregoric/bismuth subsalicylate ("Corrective

Mixture with Paregoric", manufactured by Beecham Labs); opium/ bismuth subsalicylate ("Infantol Pink", manufactured by Scherer); bismuth subgallate/pepsin and other actives ("Digestalin", manu- factured by Vortech); and bismuth subnitrate/caldum hydroxide

("Percy Medicine", manufactured by Merrick).

In spite of the efforts devoted to the problem of diarrhea, there continues to be a need for alternative safe, quick and effective methods and compositions for treating diarrhea.

The object of the present invention is therefore to provide compositions and methods useful for treating diarrhea, especially diarrhea generally characterized as travelers' diarrhea. Another object is to provide compositions and methods for treating diarrhea which reduce the duration and/or severity and/or reoccur¬ rence of diarrhea in humans or lower animals. These and other objects will become readily apparent from the detailed description which follows.

SUMMARY OF THE INVENTION The present invention relates to pharmaceutical compositions useful for treating diarrhea, especially travelers' diarrhea. These compositions comprise a bismuth-containing antidiarrheal agent (e.g., bismuth subsalicylate) and an antimotility agent selected from the group consisting of a loperamide-derived anti¬ diarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof. The present invention further relates to methods for treating diarrhea in humans or lower animals. These methods comprise concurrently administering to a human or lower animal in need of such treatment a safe and effective amount of a bismuth-containing antidiarrheal agent and an antimotility agent selected from the group consisting of a loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION (1) Antidiarrheal Compositions:

The antidiarrheal compositions of the present invention comprise one or more bismuth-containing antidiarrheal agents and one or more antimotility agents selected from the group consisting of loperamide-derived antidiarrheal agents, diphenoxylate-derived antidiarrheal agents, and mixtures thereof. Optionally, these compositions also comprise pharmaceutically-acceptable carrier materials suitable for the particular aesthetics and dose

form desired. Preferred are compositions in the form of liquid suspensions, and chewable or swallowable tablets or capsules. It is to be further recognized that such compositions may consist of simple admixtures or, depending on the agents utilized, may involve physical interaction between the agents such as a complex- ation material either preformed for use or formed in situ.

While both the bismuth-containing agents and the antimotility agents useful herein are known antidiarrheal agents, they are generally recognized as producing this result by different phy- siological mechanisms. The goal is to create an interactive effect by this combination whereby there is further enhancement of the effectiveness of each agent through their combination. This enhanced effectiveness may be observed as including faster action, reduced relapse, reduced dosing levels, and/or further enhanced safety profile.

The particular agents preferred for use herein, as well as the levels and amounts preferred therefor, are described in greater detail hereinafter, (a) Bismuth-Containinα Antidiarrheal Aoents: The pharmaceutical compositions and methods of the present invention comprise a bismuth-containing antidiarrheal agent, preferably in the form of a pharmaceutically-acceptable salt. Such bismuth-containing antidiarrheal agents include, for example, bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassiu dicitrato bis uthate, bismuth tartrate, bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof. Preferred compositions comprise bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof. Most preferred compositions of the present invention comprise bismuth subsalicylate.

The pharmaceutical compositions of the present invention typically comprise, by weight, from about 0.1% to about 99.9% of the bismuth-containing antidiarrheal agent, preferably from about 0.1% to about 75%, and most preferably from about 0.5% to about 50%.

(b) Antimotility Agents:

In addition to the bismuth-containing antidiarrheal agents described hereinbefore, the pharmaceutical compositions and methods of the present invention further comprise an antimotility agent selected from the group consisting of loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.

The term "loperamide-derived antidiarrheal agent", as used herein, means those compounds of the class of 2, 2-diaryl-4- (4'-aryl-4'-hydroxy-piperidino) butyramides, active metabolities thereof, and the pharmaceutically-acceptable salts thereof (including bismuth-containing salt complexes formed by a bismuth-containing antidiarrheal agent with a loperamide-derived antidiarrheal agent), which are effective as antidiarrheal agents, disclosed and described in detail in U.S. Patent 3,714,159, issued January 30, 1973 and U.S. Patent 3,884,916, issued May 20, 1975, both to Janssen et al., and U.S. Patent 4,824,853, issued April 25, 1989, to Wals et al., the disclosures of all these patents being incorporated by reference herein in their entirety. Preferred compounds are loperamide and the N-oxide of Toperamide, and most preferred is loperamide and/or the pharmaceutically- acceptable salt thereof (especially the hydrochloride salt thereof, as described in The Merck Index. 10th Ed., No. 5396, 1983, incorporated by reference in its entirety herein). The term "diphenoxylate-derived antidiarrheal agent", as used herein, means diphenoxylate, active metabolites thereof (e.g., difenoxine), and the pharmaceutically-acceptable salts thereof (including bismuth-containing salt complexes formed by a bismuth-containing antidiarrheal agent with a diphenoxylate- derived antidiarrheal agent), which are effective as antidiarrheal agents, disclosed and described in detail in U.S. Patent 2,898,340, issued August 4, 1959 to Janssen, and U.S. Patent 3,646,207, issued February 29, 1972 to Soudyn et al., the disclosures of both these patents being incorporated by reference herein in their entirety. Preferred compounds are diphenoxylate,

difenoxine, and the pharmaceutically-acceptable salts thereof (especially the hydrochloride salts thereof, as described in The Merck Index. 10th ed., Nos. 3325 and 3122, 1983, incorporated by reference in their entirety herein). The pharmaceutical compositions of the present invention typically comprise, by weight, from about 0.001% to about 99.9% of the antimotility agents useful herein, preferably from about 0.001% to about 10%, and most preferably from about 0.005% to about 5%. (c) PharmaceuticalIv-Acceotable Carrier Materials:

In addition to the bismuth-containing antidiarrheal agent and the antimotility agents as described hereinbefore, the pharma¬ ceutical compositions of the present invention also preferably contain one or more pharmaceutically-acceptable carrier materials. The term "pharmaceutically-acceptable carrier materials", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the pharmaceutical composition are capable of being commingled with the bismuth- containing antidiarrheal agent and the antimotility agent, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.

A variety of pharmaceutically-acceptable carriers may be included, depending on the particular dosage form to be used. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, wetting agents,

coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous and/or alcoholic solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents. Liquid oral composition typically comprise water and suspending agents, such as magnesium aluminum silicate (e.g., Veegum, manufactured by R. T. Vanderbilt Company Inc.), as part of the pharmaceutically-acceptable carrier.

Some examples of substances which can serve as phar aceuti- cally-acceptably carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl- cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; ethanol; and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium laryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabi¬ lizers, anti-oxidants, and preservatives can also be present. Other compatible pharmaceutical additives and actives (e.g., NSAI drugs; pain killers; muscle relaxants) may be included in the pharmaceutically-acceptable carrier for use in the compositions of the present invention. Techniques and compositions for making dosage forms useful herein are described in the following references, all incorporated by reference herein in their entirety; 7 Modern Pharmaceuticals. Chapters 9 and 10 (Banker and Rhodes, Ed., 1979); Lieberman, et al., Pharmaceutical Dosaoe Forms: Tablets (1981); and Ansel, Introduction to. Pharmaceutical Dosaoe Forms (2nd Edition, 1976).

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the bismuth-containing antidiarrheal agent and antimotility agent combination of the present invention is basically determined by the way the composition is to be administered. The preferred mode of administering the compo¬ sitions of the present invention is orally. The preferred unit dosage form is therefore tablets, capsules, and the like, as well as liquids and suspensions, comprising a safe and effective amount of the bismuth-containing antidiarrheal agent and the antimotility agent combination of the present invention. Pharmaceutically- acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Their selection will depend on secondary considerations like taste, cost, shelf stability, bioavailability, etc. which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art.

The pharmaceutically-acceptable carrier employed in conjunc¬ tion with the bismuth-containing antidiarrheal agent and the antimotility agent combination of the present invention is used at a concentration sufficient to provide a practical size to dosage relationship. The pharmaceutically-acceptable carriers, in total, may comprise from about 0.1% to about 99.9%, by weight, of the pharmaceutical compositions of the present invention, preferably from about 25% to about 99.9%, and most preferably from about 50% to about 99.5%.

(2) Methods for Treating Diarrhea:

Another aspect of the present invention is methods for treating diarrhea. Such methods comprise concurrently adminis¬ tering, to a human or lower animal in need of such treatment, a safe and effective amount of a bismuth-containing antidiarrheal agent and safe and effective amount of an antimotility agent selected from the group consisting of loperamide-derived anti¬ diarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof. The term "administering", as used herein, refers to any method which, in sound medical practice, delivers the bismuth- containing agent and the antimotility agent to the subject to be

treated in such a manner so as to be effective in the treatment of the diarrhea. Preferably, both these agents are administered orally, either separately or as compositions or complexes according to the present invention. The term "safe and effective amount", as used herein, means an amount of a bismuth-containing antidiarrheal agent and anti¬ motility agent, when used according to the compositions and methods of the present invention, high enough to significantly positively modify the diarrhea condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the agents of the present invention will vary with the age and physical condition of the patient being treated, the etiology and severity of- the condition, the duration of treatment, the nature of concurrent therapy, the specific agents employed, the particular pharmaceutically-acceptable carrier materials utilized, and like factors within the knowledge and expertise of the attending physician.

The methods of the present invention typically involve administering the bismuth-containing antidiarrheal agent in an amount of from about 100 g to about 5000 mg of bismuth per day, and preferably in an amount of from about 50 mg to about 1500 mg per dose. (As used herein, the quantity of the bismuth-containing antidiarrheal agents to be administered is indicated by the weight of elemental bismuth present in the dose of the bismuth-containing antidiarrheal agent. Thus, the actual weight of a dose of a bismuth-containing antidiarrheal agent will be greater than the amount of bismuth indicated.) Preferably, from about 250 mg to about 2500 mg of bismuth are administered per day, and from about 250 mg to about 1500 mg of bismuth are administered per dose. Most preferably, the bismuth-containing antidiarrheal agent is bismuth subsalicylate.

The methods of the present invention also typically involve administering the antimotility agent in an amount of from about 0.1 mg to about 20 mg per day, and from about 0.1 mg to about 5 mg per dose. Preferably from about 1 mg to about 20 mg are adminis¬ tered per day, and from about 0.5 mg to about 5 mg are

administered per dose. The preferred antimotility agents are the N-oxide of loperamide, loperamide, diphenoxylate, difenoxine, the pharmaceutically-acceptable salts thereof, and mixtures thereof. The methods of the present invention comprise administering the bismuth-containing antidiarrheal agent and the antimotility agent concurrently. The term "concurrently", as used herein, means that both types of agents are administered to the human or lower animal in need of treatment over the course of the same diarrheal episode, and preferably one or more doses of one type of agent is administered within one day of administration of one or more doses of the other type of agent. Also preferred is at least one dose of each type of agent being administered within about 60 minutes or less of each other, and more preferably within about five minutes of each other, and includes co-administration of the agent, e.g. by administering a composition or complex of the present invention.

The methods of the present invention in which the agents are administered concurrently comprise any dosing regimen in which part or all of the dosing of the agents is performed concurrently. Thus, for example, methods comprising concurrent dosing of the agents include:

(1) 2 days of a pharmaceutical composition of the present invention taken after each loose stool;

(2) 4 tablets of a bismuth subsalicylate-containing compo- sition and 1 tablet of a 2 milligram lopera ide- containing composition administered within 5 minutes of each other QID.

For the methods of the present invention, the duration of administration of the agents will typically vary according to the severity of the diarrhea being treated, but usually will be within the range of from about 1 to about 3 days, and may require as few as one dose of a pharmaceutical composition according to the present invention.

The following examples further describe and demonstrate the preferred embodiments within the scope of the present invention.

The examples are given solely for the purpose of illustration, and

are not to be construed as limitations of the present invention since many variations thereof are possible without departing from its spirit and scope.

EXAMPLE 1 Liquid Pharmaceutical Composition A composition of the present invention in liquid form suitable for oral administration is prepared using conventional methods and having the following components.

Components Weight %

Veegum* 0.985

Methylcellulose2 1.079

Bismuth subsalicylate 1.75

Loperamide HC1 0.0066

FD&C red #3 0.0364

FD&C red #40 0.00539

Sodium saccharin 0.06081

Sodium salicylate 0.05983

Salicylic acid 0.07062

Methyl salicylate 0.060

Peppermint oil 0.005

Purified water Q.S.

- Magnesium aluminum silicate manufactured by R.T. Vanderbilt

Company, Inc. 2 Methocel A*, supplied by The Dow Chemical Company.

This composition may be prepared by first mixing the Veegum in chilled water, and then adding to this mixture a warm aqueous slurry of methylcellulose followed by FD&C red #3, bismuth sub¬ salicylate slurry, FD1C red #40, sodium saccharin, sodium salicylate, peppermint oil, and a slurry of salicylic acid and methyl salicylate. Finally, the loperamide hydrochloride salt is added followed by sufficient water to dilute the composition to the desired final weight, and the composition is mixed to homo¬ geneity.

Ingestion of 2 tablespoonfuls (approximately 30ml containing about 525 mg of bismuth subsalicylate and 2 mg of loperamide) of this liquid four times per day is effective for treating diarrhea. Similarly, an effective composition may also be prepared and orally administered by using the N-oxide of loperamide, diphen¬ oxylate hydrochloride, or difenoxine hydrochloride in place of the loperamide hydrochloride salt in the above formulation at the .same concentration.

EEAHPIE I Method for Treating Diarrhea

A human subject experiencing diarrhea is treated according to the following regimen. Initially, the patient is treated with four teaspoonfuls (20 ml) of a loperamide hydrochloride-containing liquid composition (Imodium ^® A-D, sold by McNeil Consumer Products Company; 1 mg loperamide HC1 per teaspoonful) and, within about 5 minutes thereof, two tablespoonfuls (30 ml) of a bismuth sub- salicylate-containing liquid composition (Pepto-Bismol*, sold by The Procter & Gamble Company; 262.5 mg bismuth subsalicylate per tablespoon). Thereafter, 2 teaspoonfuls (10 ml) of the loper- amide-containing composition is taken after every loose stool to a maximum of 8 teaspoonfuls per day; and 2 tablespoonfuls (30 ml) of the bismuth subsalicylate-containing composition is taken every 30 minutes to a maximum of 8 times per day. Within 2 days the patient's diarrhea is stopped and does not recur following cessation of treatment. Similar results may be obtained by using diphenoxylate-containing liquid product (Lomotil*, sold by Searle & Company 2.5 mg diphenoxylate HC1 per teaspoonful) at a dose level of two teaspoonfuls (10 ml) initially and thereafter after every loose stool to a maximum of 8 teaspoonfuls per day.